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Regulation of hairy-cell survival through constitutive activation of mitogen-activated protein kinase pathways

Oncogene volume 22, pages 2272–2284 (2003)Cite this article

Abstract

The hairy cells (HCs) of hairy-cell leukemia are intrinsically activated mature clonal B cells. The aims of this study were to gain further insights into the nature of this activation and to assess its importance for the prolonged HC survival in this chronic disease. We show that HCs contain phosphorylated/activated p38 MAPK, JNK and ERK1/ERK2 (ERK1/2). PKC inhibitors increased the activation of p38 and JNK, but reduced the phosphorylation of ERK1/2. Moreover, PKC inhibition resulted in cell death; cell death was also observed when the activation of ERK1/2 in HCs was abrogated with an inhibitor of MEK1/2 activation. In addition to PKC, active Src kinase was also shown to be involved in the maintenance of Raf-independent ERK activation in HCs. During cell culture on a nonadherent surface, ERK phosphorylation was sustained, while phosphorylation of p38 and JNK decreased. This decrease was not observed in HCs cultured on vitronectin (VN), indicating that p38/JNK activation is probably a consequence of in vivo HC interaction with VN present in abundance in the red pulp of the spleen. Taken together, these results suggest that active p38/JNK make HCs susceptible to apoptosis, but the cells are effectively rescued by ERK activation involving constitutively active PKC and Src. These findings are relevant for the understanding of the prolonged cell survival of HCs and their selective sensitivity to some chemotherapeutic agents.

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Acknowledgements

We are grateful to Dr UR Rapp (University of Würzburg, Germany) for the generous gift of the recombinant GST-(K97M) MEK, mAb 12S and the antibody against recombinant c-Raf. This work was supported by the Leukaemia Research Fund (UK) and the Northwest Cancer Research Fund, UK.

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  1. Department of Haematology, Royal Liverpool University Hospital, University of Liverpool, Daulby Street, Liverpool, L69 3GA, UK

    Aura S Kamiguti, Robert J Harris, Joseph R Slupsky, Peter K Baker, John C Cawley & Mirko Zuzel

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Correspondence to Aura S Kamiguti.

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Kamiguti, A., Harris, R., Slupsky, J. et al. Regulation of hairy-cell survival through constitutive activation of mitogen-activated protein kinase pathways. Oncogene 22, 2272–2284 (2003). https://doi.org/10.1038/sj.onc.1206398

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